In a randomised, open-label, international, phase III CheckMate 8HW study, conducted in patients with microsatellite instability (MSI)-high or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC), treatment with nivolumab plus ipilimumab showed improvement in progression-free survival (PFS) versus nivolumab across all lines of therapy.
The results support nivolumab plus ipilimumab as a potential new standard of care according to Prof. Thierry André of the Sorbonne Université, Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris in Paris, France and colleagues, who presented the findings at the 2025 ASCO Gastrointestinal Cancers Symposium along with a simultaneous publication on 25 January 2025 in The Lancet.
Approximately 4-7% of patients with mCRC have tumours with MSI-high or dMMR status that is associated with poor outcomes to chemotherapy with or without targeted therapies. Pembrolizumab showed improved PFS versus chemotherapy in patients with MSI-high or dMMR mCRC in the first-line setting. Furthermore, in the phase II, non-randomised CheckMate 142 study, nivolumab plus ipilimumab showed promising efficacy and manageable safety in previously treated and untreated immunotherapy-naive patients with MSI-high or dMMR mCRC.
The authors wrote that indirect comparisons of non-randomised cohorts within CheckMate 142 suggested better outcomes with nivolumab plus ipilimumab than with nivolumab monotherapy and underscored the importance of determining the potential benefit of dual-agent immunotherapy versus single-agent immunotherapy in the treatment of MSI-high or dMMR mCRC in a randomised setting.
The ongoing phase III CheckMate 8HW study was designed to evaluate nivolumab plus ipilimumab compared with nivolumab monotherapy or chemotherapy with or without targeted therapy in patients with MSI-high or dMMR mCRC. At the previous prespecified interim analysis with a median follow-up of 31.5 months, nivolumab plus ipilimumab showed superior PFS compared with chemotherapy in the first-line setting with a median PFS not reached (95% confidence interval [CI] 38.4 to not estimable) versus 5.9 months (95% CI 4.4-7.8) and hazard ratio (HR) of 0.21 (95% CI 0.13-0.35; p < 0.0001 with the use of a two-sided stratified log-rank test), meeting one of the dual primary endpoints of this study. PFS at 24 months was 72% with nivolumab plus ipilimumab versus 14% with chemotherapy.
In the latest report, the study team announced the results from the prespecified interim analysis of the other dual primary endpoint of PFS for nivolumab plus ipilimumab compared with nivolumab monotherapy across all lines of treatment. Additionally, they presented longer follow-up results of PFS for nivolumab plus ipilimumab compared with chemotherapy in the first-line setting.
CheckMate 8HW is conducted at 128 hospitals and cancer centres across 23 countries. Immunotherapy-naive adult patients with unresectable or mCRC across different lines of treatment and MSI-high or dMMR status per local testing were randomly assigned 2:2:1 to nivolumab plus ipilimumab, nivolumab, or chemotherapy with or without targeted therapies.
The dual independent primary endpoints were PFS by blinded independent central review (BICR) with nivolumab plus ipilimumab versus chemotherapy (first-line) and PFS by BICR with nivolumab plus ipilimumab versus nivolumab (all lines) in patients with centrally confirmed MSI-high or dMMR mCRC.
Between 16 August 2019 and 10 April 2023, 354 patients were randomly assigned to nivolumab plus ipilimumab and 353 to nivolumab alone. A total, 296 of 354 patients (84%) in the nivolumab plus ipilimumab group and 286 of 353 patients (81%) in the nivolumab group were centrally confirmed to have tumours with MSI-high or dMMR status.
At the data cut-off on 28 August 2024, median follow-up (from randomisation to data cut-off) was 47.0 months (interquartile range 38.4 to 53.2). Nivolumab plus ipilimumab treatment showed significant and clinically meaningful improvement in PFS versus nivolumab (HR 0.62, 95% CI 0.48–0.81; p = 0.0003). Median PFS was not reached with nivolumab plus ipilimumab (95% CI 53.8 to not estimable) and was 39.3 months with nivolumab (95% CI 22.1 to not estimable).
The objective response rate (ORR) observed in CheckMate 8HW for nivolumab plus ipilimumab across all lines of treatment in centrally confirmed MSI-high or dMMR mCRC is the highest reported in a randomised setting. Responses to treatment were durable in both the nivolumab plus ipilimumab and nivolumab groups, and median duration of response (DoR) was not reached in both groups.
The authors commented that high complete response rate in this study suggests that cure can be achieved in a proportion of patients, even in a metastatic setting. Future exploration of this hypothesis could include potential landmark analyses of PFS and overall survival (OS) by best overall response, as well as biomarker analyses assessing correlations between radiographic response and circulating tumour DNA.
Treatment-related adverse events of any grade occurred in 285 of 352 patients (81%) who received nivolumab plus ipilimumab and in 249 of 351 patients (71%) who received nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 78 (22%) and 50 patients (14%), respectively. There were three treatment-related deaths: one event of myocarditis and pneumonitis each in the nivolumab plus ipilimumab group and one pneumonitis event in the nivolumab group.
Due to the relatively shorter duration of minimum follow-up for the current interim analysis, some secondary endpoints, such as DoR, remain immature; these will be addressed with additional follow-up. Patient numbers in some of the prespecified subgroups were low, limiting data interpretation. Although subgroup analyses for assessment of PFS and ORR by line of treatment would have been of interest, treatment lines remain masked at this time because these data are not yet mature, in line with the hierarchical testing plan. Furthermore, OS data remain masked at this time and will be valuable to further contextualise the study results.
In an accompanied comment, Drs. S Daniel Haldar and Scott Kopetz of the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston, TX, US wrote that CheckMate 8HW features an elegant statistical design with hierarchical testing of multiple endpoints to minimise the type I error rate while enabling multiple clinically relevant comparisons. The results are novel and clinically relevant, representing the first randomised phase III data showing that dual immune checkpoint blockade improves outcomes compared with single-agent anti-PD1 therapy in patients with MSI-high or dMMR mCRC.
Although the results of this study are encouraging, a limitation is the relatively high rate of discordance between local testing and central confirmation of MSI-high or dMMR status. This discordance highlights the imperfections of the assays used and supports the ESMO recommendations for two testing methodologies and referral to an expert diagnostic centre in cases of uncertainty. With the advent of immunotherapy in this setting, the use of accurate and reliable biomarker testing, including orthogonal confirmation by next-generation sequencing is crucial for patient selection.
The study was funded by Bristol Myers Squibb and Ono Pharmaceutical.
References
- André T, Elez E, Lenz H-J, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol 43, 2025 (suppl 4; abstr LBA143).
- André T, Elez E, Lenz H-J, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. The Lancet; Published online 25 January 2025. DOI: https://doi.org/10.1016/S0140-6736(24)02848-4
- Haldar SD, Kopetz S. Dual checkpoint blockade for microsatellite instability-high colorectal cancer. The Lancet; Published online 25 January 2025. DOI: https://doi.org/10.1016/S0140-6736(25)00144-8